Human Molecular Genetics, 2002, Vol. 11, No. 18 2119-2127
© 2002 Oxford University Press
A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype
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1Department of Medicine, Faculty of Medicine and Health Science, University of Auckland, New Zealand, 2Molecular Genetics Laboratory, Auckland Hospital, Auckland, New Zealand, 3Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital, Adelaide, South Australia, 4School of Biological Sciences, University of Auckland, Auckland, New Zealand and 5Department of Pediatrics, Friedrich-Schiller-University, Jena, Germany
Received April 24, 2002; Accepted June 24, 2002
Idiopathic hyperphosphatasia is an autosomal recessive bone disease characterized by deformities of long bones, kyphosis and acetabular protrusion, increasing in severity as affected children pass through adolescence. Biochemical and histological evidence indicate that there is extremely rapid bone turnover, with indices of both bone resorption and formation greatly increased. A genome-wide search, in a family with three children affected by idiopathic hyperphosphatasia, suggested linkage to a locus on the long arm of chromosome 8 (8q24). The gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate, given the critical role of OPG in regulating osteoclast development. All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue. Their parents (who were first cousins) were heterozygous for the mutation. Recombinant wild-type and mutant OPG cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wild-type OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation. This description of abnormal OPG function in humans expands the spectrum of genetic bone diseases arising from perturbations of the OPG/RANK-L/RANK system that regulates osteoclastogenesis.
* To whom correspondence should be addressed. Tel: +64 93797440; Fax: +64 93022101; E-mail: t.cundy@auckland.ac.nz
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present addresses: M. Hegde, Diagnostic Sequencing Laboratory, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
R. Wallace, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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